1. Field of the Invention
The invention generally relates to improved lung deposition of aerosols. In particular, in one embodiment, the invention provides aerosol formulations which are pharmaceutically engineered and formulated to contain hygroscopic excipients, and in another embodiment or a variation of the first embodiments, provides methods, apparatuses and systems for improved delivery of aerosols to the lungs using dual stream nasal delivery.
2. Background of the Invention
Nanoparticle aerosol drug delivery presents an advantageous route of administration for both locally and systemically acting pharmaceuticals. Inhaled nanoparticles in the size range of 40-1000 nm are capable of efficiently penetrating the mouth-throat (MT), nasal, and tracheobronchial (TB) regions of the lungs. Indeed, this nanoparticle size is optimum for transport into the peripheral lung regions, including the alveoli. However, once in the deep lung regions, the nanoparticles lack sufficient mass and inertia to deposit by sedimentation and impaction. Nanoparticles greater than approximately 40 nm also lack sufficient Brownian motion to deposit by diffusion. As a result, inhaled nanoparticles in the size range of 40-1000 nm often do not deposit in the lungs and are exhaled. Only a small fraction of inhaled nanoparticles actually deposit within the peripheral lung regions, with the majority, (about 70%) being exhaled (see FIG. 1).
The typical prior art solution to this problem is to deliver nanoparticles in conventional aerosol formulations, e.g. suspended in nebulized droplets, formulated as suspended particles in metered dose inhalers or combined with large carrier particles in a dry powder inhaler system. The primary limitations of these systems include the same drawbacks encountered by the current generation of inhaled pharmaceuticals. Namely, they are often deposited in the lung at very low deposition efficiencies. Perhaps as significant as the quantity of drug deposited is the large inter- and intra-subject variability that is often observed with these medicinal aerosols and the associated dose delivered to the lung. This is a particular problem for drugs with narrow therapeutic windows where accurate and reproducible dosing is essential. These commonly used inefficient aerosol drug delivery systems have particle sizes in the range of about 3-5 μm. For the delivery of 3-5 μm particles, deposition in the extrathoracic and upper TB airways may be significant (e.g. 80%, see FIG. 1). This deposition may be further enhanced by inhaler momentum effects, resulting in up to approximately 90% drug loss in the MT. Clearly, the present systems used for the delivery of pharmaceutical nanoparticles to the lungs are not optimal and result in poor drug delivery efficiency.
Non-invasive ventilation (NIV) is currently a form of standard care for patients suffering from respiratory insufficiency, sleep apnea, chronic obstructive pulmonary disease (COPD) and more severe acute and chronic respiratory failure. A common form of NIV is non-invasive positive pressure ventilation (NPPV) in which a mask or other interface supplies positive pressure flow to the nose and mouth. Extensive reviews have indicated the benefits of NPPV in adults and children. For less severe respiratory insufficiency and support, low-flow therapy (LFT) through a nasal cannula is common practice. In addition, high-flow therapy (HFT) has recently been introduced in which air or blended oxygen is preconditioned with heat and water vapor (humidity) to allow continuous delivery through a nasal cannula up to flow rates of 40 L/min. This approach is currently being applied to treat conditions such as pulmonary edema, COPD, bronchiectasis, and acute respiratory distress syndrome (post-intubation).
Patients receiving NIV typically have underlying respiratory and systemic conditions that can be effectively treated with a range of drugs administered non-invasively as pharmaceutical aerosols. However, both in vivo and in vitro studies have illustrated that high drug aerosol deposition losses occur in NIV tubing and delivery systems, resulting in very low delivery efficiencies on the order of <1-7% in both adults and children. Aerosol drug delivery to the lungs via NIV also employs conventional drug delivery devices (e.g. nebulizers and metered dose inhalers), that generate aerosols with relatively large particle sizes (3-5 μm). This large aerosol particle size results in high delivery system and nasal losses during NIV and may result in high variability in the amount of drug aerosol reaching the lungs. This is especially problematic for therapeutic substances with narrow therapeutic indices, and in fact, NIV may unfortunately not be appropriate for many next-generation medications, some of which have relatively narrow therapeutic windows. Moreover, high variability in delivery rates impacts the assessment of clinical trial results since the actual dose reaching a patient cannot be consistently established. However, despite low efficiency and associated problems, this current standard of care is often preferable to the alternative of temporarily halting NIV therapy for 10-30 minutes up to 2-8 times per day for administration of essential nebulized medications.
Clearly, improved methods for the pulmonary delivery of therapeutic agents are a desideratum in the medical field.